MSR for 07 12 12 no methadone by 8b6X47

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									MEDICATION SUPPORTED RECOVERY



Steven Kipnis MD, FACP, FASAM
Medical Director, NYS OASAS
WHAT IS THE MOST
 COMMONLY USED
 PSYCHOACTIVE
 SUBSTANCE IN THE
 WORLD?
WHAT IS THE MOST
  COMMONLY USED
  PSYCHOACTIVE
  SUBSTANCE IN THE
  WORLD?
WHAT IS THE FIRST SPORT TO
  TEST FOR DRUGS?
WHAT IS THE FIRST SPORT TO
  TEST FOR DRUGS?
                 Mystery of Change
•   Why do people who seem to want to stop using alcohol and drugs
                         continue to use?
    o   Motivation
         •   Ambivalence about initiating change
         •   Changes in level of motivation
    o   Environmental and social influences
         •   Exposure to substances or reminders of using
         •   Spending time with social group that continues to use
    o   Psychosocial stressors
         •  Everyday life problems (e.g., work, family, finances)
         •  Major life problems (e.g., medical conditions, homelessness)
    o   Psychological Disorders
         •  Comorbid anxiety, depression, PTSD
                      Mystery of Change

      •What factors affect treatment and recovery efforts?

           family dynamics            coping skills


12 step involvement         cognitive impairment      genetics


co-dependency          prolonged withdrawal     social support

  reward contingencies       problem severity

                             changes in
                           brain chemistry
                       A Complex Disorder


                             Neurobiological
                           dysregulation should
                              be treated with
                            pharmacotherapy




Nutritional deficits
 should be treated
                            Substance               Dysfunctional
   with dietary            Dependence              behavior should
                                                    be addressed
improvements and
                                                  with psychosocial
 supplementation                                    interventions
         Changes in Brain Chemistry
•   Drugs of abuse produce their effects by altering brain
    chemistry and structure.
•   Neurotransmitters and associated receptors responsible
    for everyday functions are altered by the consumption
    of drugs.
• Rats give THC as adolescents
• Rats exposed to heroin as adults
   o   THC+ rats used heroin at a higher rate than THC – exposed rats
• Same is true for nicotine
• Protein changes on autopsy
       Adults Who Initiate Alcohol Use Before Age 21
    More Likely to Abuse or Become Dependent on Alcohol

•   Early onset of alcohol use is
    associated with a greater likelihood of
    developing alcohol abuse or
    dependence at a later age, according
    to data from the National Survey on
    Drug Use and Health (NSDUH).                                 Percentage of Adults (Ages 21 or Older)
•   Those who first used alcohol at or                           Who Abused or Were Dependent on
                                                                 Alcohol in the Past Year, by Age of First
    before the age of 14 were nearly four                        Alcohol Use, 2009
    times more likely to meet the criteria
    for past year alcohol abuse or
    dependence than those who started                   20%
    using alcohol between the ages of 18                16%
                                                                  16.5%
    and 20 (16.5% vs. 4.4%) and more
    than six times more likely than those               12%
    who started using alcohol at or after                                         9.4%

    age 21 (16.5% vs. 2.5%).                            8%

•   These findings illustrate the need for              4%
                                                                                                    4.4%
                                                                                                                 2.5%
    alcohol education and prevention
    efforts as early as middle school.                  0%
                                                               14 or Younger     15 to 17          18 to 20    21 or Older

                                                                                    Age First Used Alcohol




                      SOURCE: Adapted by CESAR from Substance Abuse and Mental Health Services
                      Administration, Results from the 2009 National Survey on Drug Use and Health: Detailed
                      Tables, 2010. Available online at http://oas.samhsa.gov/WebOnly.htm#NSDUHtabs.
Early Marijuana Use Related to Later Illicit Drug Abuse and
                     Dependence

                                              Percentage of Adults (Ages 18 or Older)
                                              Who Abused or Were Dependent on Illicit
• Adults who first started using               Drugs in the Past Year, by Age of First
  marijuana at or before the age                       Marijuana Use, 2009
  of 14 are most likely to have
  abused or been dependent on
  illicit drugs in the past year,       20%

  according to data from the            16%

  National Survey on Drug Use           12%
                                                 12.6%

  and Health (NSDUH). Adults
                                        8%
  who first used marijuana at                                        6.6%

  age 14 or younger were six            4%
                                                                                           2.1%
  times more likely to meet the         0%
                                              14 or Younger          15 to 17            18 or Older
  criteria for past year illicit drug
                                                              Age First Used Marijuana
  abuse or dependence than
  those who first used marijuana
  when they were 18 or older
  (12.6% vs. 2.1%)
                          Dopamine and Reward

•Dopamine is one of the primary neurotransmitters in the experience of pleasure
and the maintenance of addiction.
                                                              Many drugs of abuse stimulate
                                                              neurons in the ventral tegmental
                                                              area, releasing dopamine in the
                                                              nucleus accumbens and prefrontal
                                                              cortex.

                                                              Nearly all drugs of abuse increase
                                                              dopamine in the nucleus
                                                              accumbens, which appears to be
                                                              the primary reinforcement center
                                                              of the brain.
  Image Credit: NIDA : “The Neurobiology of Drug Addiction”
NAc            VTA
                                                                 Amphetamine
                                                                 Cocaine
                                                                 Opioids
                   GLU     HIPP                                  Cannabinoids
         FCX                                                     Phencyclidine
                           AMYG   CRF
                           GLU             5HT
      GABA
                                  OPIOID   OPIOID
       ENK                                GABA
                                   GABA
        VP
                                      DYN         5HT
             OFT
                                     DA
                             BNST                       GABA

                     ABN                                     NE LC
                                                                            PAG
                                    HYPOTHAL                NE                    END
                                                                 LAT-TEG
                                          Opioids                                    To
                                          Ethanol                          5HT     dorsal
                                          Barbiturates                       Raphé horn
                                          Benzodiazepines
                                          Nicotine                                RETIC
REWARD CIRCUIT
Initial Pleasure
Craving
Generalizes to other Substances
Binge Behavior
Decreased Inhibitions
Impaired Motor Control
Loss of Control
Family Problems
Poor Performance at Work
Neglecting Hygiene
Major Loss of Focus
Turn Loss of Focus into Financial
          Opportunity
Regrets
Medication Supported Recovery –
 Homer on a Diet - Eating a Rice
             Cake
                            Natural Reward vs.
                         Substance-Induced Reward


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           •Dopamine transmission:                          •            Dopamine transmission:
              •Natural reinforcer                               •          Substance-induced


•   People seek out experiences that feel good.    •   Nearly all drugs of abuse also increase
•   These experiences are “natural reinforcers.”       dopamine availability.
                                                   •   Dopamine release in the nucleus accumbens
•   Natural reinforcers stimulate release of           is 3-5 times greater for substances than
    dopamine.                                          natural reinforcers.
          Down-Regulation of Dopamine




  •Dopamine transmission:     •Dopamine transmission:      •Dopamine transmission:
   •Natural reinforcer         •Substance-induced            •Down-regulated



•Continual activation of the dopamine pathway alters the availability of dopamine.

•The reduction or down-regulation in dopamine availability has a blunting effect
on the natural reward circuit.
IT IS NOT ABOUT THE BRAIN BEING ADDICTED TO A
     SUBSTANCE, IT’S ABOUT THE BRAIN BEING
        ADDICTED TO ITS OWN CHEMISTRY
Neurotransmitters, Medications and the
           Receptor Site
AGONIST
PARTIAL AGONIST
ANTAGONIST
           ADDICTION MEDICINES
•   ACAMPROSATE       •   NALTREXONE
•   ANTABUSE          •   NALOXONE
•   ANTICONVULSANTS   •   NEURONTIN
•   BACLOFEN          •   NICOTINE REPLACEMENT
•   BUPRENORPHINE         THERAPIES
•   CLONIDINE         •   SSRI’S
•   METHADONE/LAAM    •   ZYBAN
                      •   VACCINES
                      BARRIERS

•   MEDICATION
•   PATIENT
•   PHYSICIAN/NURSE
•   COUNSELOR
•   PROGRAM
•   SYSTEM
                          BARRIERS

• MEDICATION
  o   INSUFFICIENT EVIDENCE REGARDING EFFICACY
  o   CONTRADICTORY EVIDENCE
  o   TOO EXPENSIVE
       • NALTREXONE $2.50 - 4.43 PER DAY
  o   CORRECT DOSE?
  o   SIDE - EFFECTS
                         BARRIERS

• MEDICATION
  o   CANDIDATE SELECTION
       • TOOLS NEED TO BE RESEARCHED - WHO WILL BENEFIT MOST?
  o   POTENTIAL FOR ABUSE
  o   POTENTIAL FOR DIVERSION
  o   “MAGIC BULLET THEORY”
  o   DELIVERY SYSTEM
                      BARRIERS

• PATIENT
  o   COMPLIANCE
  o   SELECTION
  o   STIGMA
  o   COST/INSURANCE COVERAGE
                        BARRIERS

• PHYSICIAN/NURSE
  o   LACK OF AWARENESS
  o   LACK OF TRAINING
  o   LACK OF ONGOING TECHNICAL ASSISTANCE
  o   DO NOT PROMOTE USE
  o   MD’S NEEDED AT ALL PROGRAMS
  o   EXTRA WORK
       • OBSERVATION TIME
                           BARRIERS

• COUNSELOR
  o   LACK OF AWARENESS
  o   LACK OF TRAINING
  o   COUNSELORS IN RECOVERY
       • “NOT THE WAY I DID IT”
  o   MORE WORK
       • AFTERCARE
                         BARRIERS

• PROGRAM
  o   NEED PHYSICIAN SERVICES
  o   NEED TO INCREASE COMMUNICATION BETWEEN PHYSICIANS
      AND COUNSELORS
  o   NEED LINKAGE TO MD AFTERCARE
       • MONITOR DRUG LEVELS
       • MONITOR SIDE - EFFECTS
       • WRITE RX
  o   ENDANGERS PROGRAM INTEGRITY (THERAPEUTIC COMMUNITY)
                         BARRIERS

• SYSTEM
  o   REGULATIONS NEED TO BE CHANGED
       • WHO WILL PAY FOR MD SERVICES
  o   NEED INCREASE IN EDUCATION AND T.A.
  o   PRIVATE MD’S NEED TO BE ABLE TO LINK TO THE SYSTEM
  o   NEED OUTCOME DATA
       Does Treatment Work?
   Medications +
    psychosocial
    therapy both
    benefit brain
    function and
    recovery.
   Each affects
    different parts
    of brain and in
    opposite ways.

                      PET scans adapted and retouched from Goldapple et al. 2004
Medications for Alcohol Dependence

 Antabuse®          ReVia®          Campral®                          VIVITROL®
  (disulfiram)1    (naltrexone)2     (acamprosate)3              (naltrexone for extended-
                                                                          release
                                                                  injectable suspension)4




30 tabs/month*    30 tabs/month*    180 tabs/month*                           1/month
    (1 tab/day)       (1 tab/day)     (2 tabs, 3x/day)



    1951              1994                2004                                     2006


                                            1. Antabuse full Prescribing Information. Odyssey Pharmaceuticals, Inc.
                                               2. ReVia full Prescribing Information. Duramed Pharmaceuticals, Inc.
                                                       3. Campral full Prescribing Information. Merck Santé s.a.s.
                                                       4. VIVITROL full Prescribing Information. Alkermes, Inc.
     Current Pharmacotherapies


2 general categories:
- anticraving (naltrexone, acamprosate)
- alcohol-aversion (dilsufiram)

    Pharmacotherapies should be used in
  combination with psychosocial treatment.
Opioid Receptors and Alcohol
        Dependence




                          1. Gianoulakis C. Alcohol Health Res World. 1998;22:202-210.
                2. Woodward JJ. Principles of Addiction Medicine. 3rd ed. 2003:101-118.
      Naltrexone: Adverse Effects

- generally well tolerated

-minor side effects in 10% patients: nausea, dizziness and
headache
-Start with lower dose 12.5 – 25 mg and build up to 50mg
  Naltrexone: Contraindications
patients receiving long-term opioids
        - therapy for chronic pain
        - methadone/buprenorphine maintenance therapy
        - heroin dependence

patients with acute hepatitis or hepatic failure
        - hepatotoxicity shown with high doses

patients with renal impairment
        - use caution

FDA pregnancy C category
       - no complete human studies done
patients with allergy to naltrexone
            Candidates for Naltrexone

• Good candidate:
   o   High motivation
   o   Failed agonist treatment
   o   Successful agonist treatment but want a change
   o   Detox easily but relapse often
   o   Early in disease
   o   Positive family history
   o   Very high craving level
• Bad candidate:
        • History of overdose
        • When patient is opiate free do not feel normal
                          Vivitrol

•   Depot naltrexone
•   Approved for alcohol and opiate dependence
•   380mg/month
•   Cost is a factor – but it improves compliance
    Effects of Naltrexone Treatment for Alcohol-Related Disorders on
                Healthcare Costs in an Insured Population


•   Henry R. Kranzler et al Alcoholism Clinical and Experimental Research June 2010

•   Objective: To determine the impact of treatment with oral naltrexone on healthcare costs in
    patients with alcohol-related disorders.
•   Methods: Using data from the MarketScan Commercial Claims and Encounters Database for
    2000–2004, we identified a naltrexone group (with an alcohol-related diagnosis and at least one
    pharmacy claim for oral naltrexone) and two control groups. Alcohol controls had an alcohol-
    related diagnosis and were not prescribed an alcoholism treatment medication. Nonalcohol
    controls had no alcohol-related diagnosis and no prescription for an alcoholism treatment
    medication. The control groups were matched three to one to the naltrexone group on
    demographic and other relevant measures. Healthcare expenditures were calculated for the 6-
    month periods before and after the index naltrexone drug claim (or matched date for controls).
    Univariate and multivariate analyses were used to compare the groups on key characteristics and
    on healthcare costs.
•   Results:
     o   Naltrexone patients (n = 1,138; 62% men; mean age 45 ± 11 years) had significantly higher total healthcare
         expenditures in the pre-index period than either of the control groups.
     o   In the postindex period, naltrexone patients had a significantly smaller increase than alcohol controls in total
         alcohol-related expenditures.
     o   Total nonalcohol-related expenditures also increased significantly less for the naltrexone group than for the
         alcohol control group.
•   Conclusions: Although prior to treatment patients with alcohol-related disorders had higher
    healthcare costs, treatment with oral naltrexone was associated with reductions both in alcohol-
    related and nonalcohol-related healthcare costs.
                      Vivitrol Studies

• 25% reduction in heavy drinking when compared to
  placebo group
   o   In 4 day lead in maintained abstinence was 32% in the treatment
       group vs 11% in the placebo group (all got behavioral treatment)
   o   Better abstinence rates with 7 day lead in
• Good adherence to medication
   o   74% had 4 injections
   o   64% had 6 injections
                             New Uses

• Nicotine dependence – men did better than women
   o   Women also don’t do as well with NRT: smoke for different
       reasons than men??
• Cannabis dependence
   o   Actually increased the high and increased cravings
• Amphetamine/Stimulant dependence
   o   Decreased cravings and less depression and anxiety
   o   Decreased cocaine use if also used opiates
• Low dose naltrexone when coming off agonists
        • Too long a period after off agonists and start of vivitrol (can be
          10days before naltrexone and 15 daysbefore vivitrol with
          methadone tapers)
       Acamprosate (Campral®)

Modulator of neuronal excitatory processes
Approved (FDA) in July 2004

Evidence suggests that
acamprosate increases
abstinence and lowers the
frequency of drinking in
patients with alcohol use
problems.
     Acamprosate: Mechanism of Action
                          neuronal processes:
                               excitatory (glutamate)
                               inhibitory (GABA)




acamprosate
     Acamprosate: Pharmacokinetics
Metabolism
 None
Elimination
 Kidney = 100% as unchanged acamprosate
Dose
 333mg (2 tabs) TID
   Acamprosate: Adverse Effects

- well tolerated

-minor side effects: diarrhea, dizziness
Acamprosate: Drug Interactions


       None?
Acamprosate: Contraindications
patients with severe renal impairment or renal failure
        - reduced dosage for moderate renal impairment

patients with sulfite hypersensitivity

FDA pregnancy C category
       - teratogenic in animals

patients breastfeeding

patients with suicidal ideation
        - caution
  Anticraving Pharmacotherapies

                 CRAVING
       (irresistible desire to drink)

       naltrexone             acamprosate



    conditioned cues            conditioned cues
associated with drinking   associated with withdrawal
  Alcohol - Deterrent Therapy




deterrent
 therapy    +
         Disulfiram (Antabuse®)

Interferes with the hepatic oxidation of acetyladehyde
Approved (FDA) in 1951 after discovery by Danish
scientists in the 1930’s as an antihelminthic (flatworms)


Early evidence suggested
that disulfiram can help
patients to remain sober if
taken under supervision.
  Disulfiram: Mechanism of Action

  alcohol                            alcohol
                  alcohol
               dehydrogenase

acetaldehyde
                acetaldehyde
                               acetaldehyde
               dehydrogenase

  acetate
                        disulfiram
  carbon
  dioxide
                         Dosing

•   Rapidly absorbed
•   Peak plasma levels in 9 hours
•   Usual dose is 250 mg qd
•   The patient should be alcohol abstinent for a minimum of
    48 hours before starting disulfiram
            Disulfiram: Efficacy


                        ?

Double-blinded studies are not possible with disulfiram.
Disulfiram is usually only an adjunct therapy.
    Disulfiram: Adverse Effects
Severe reaction after alcohol ingestion:
problems breathing, severe fall in blood pressure,
heart attack, acute congestive heart failure,
unconsciousness, seizure, and death

Sides effects even in the absence of
alcohol:
skin rash, drowsiness, headache, a metallic or garlic
aftertaste, and psychotic reactions (confusion,
extreme fear, or hallucinations)
Rare hepatotoxicity – occurs 1/25,000 patient years
of treatment (mechanism unknown)
    Disulfiram: Adverse Effects
Psychosis and Hallucinations due to interference
with dopamine hydroxylase
(dopamine can’t be metabolized into NE) so more
dopamine = psychotic reactions
   Disulfiram: Drug Interactions
Anything that contains alcohol:
- aftershaves, cologne, antiperspirants, hair dyes/rinses, mouthwashes
- cough and cold medicines, some vitamin preparations
- vinegar, cakes
       Use in Cocaine Dependence

• FDA approved for alcohol dependence
• 80% of cocaine dependent patients have alcohol
  dependence – can decrease in alcohol use decrease
  cocaine use?
• Inhibits dopamine – B – hydroxylase, an enzyme which
  catalyzes the rate limiting step in conversion of
  dopamine to norepinephrine (increase dopamine which
  may be needed in the depleted cocaine patient)
• In the human laboratory model, disulfiram elevates
  cocaine plasma levels through an unknown mechanism
            ANTICONVULSANTS
• USED IN PAIN MANAGEMENT AND WITHDRAWAL
  TREATMENT
  o   CARBAMAZEPINE (TEGRETOL®)
       • IN 3 TRIALS, AS EFFECTIVE AS BENZODIAZEPINES FOR
         MILD TO MODERATE ALCOHOL WITHDRAWAL
       • ? IF IT REDUCED DRINKING BEHAVIOR IMMEDIATELY
         POST WITHDRAWAL TREATMENT
       • ? IF REDUCED COCAINE CRAVING 5 STUDIES POSITIVE
         AND 5 WERE NEGATIVE (200-1000MG/D)
             ANTICONVULSANTS

• CARBAMAZEPINE (TEGRETOL®)
  o   NO RESPIRATORY DEPRESSION
  o   NO INHIBITION OF LEARNING, UNLIKE BENZODIAZEPINES
  o   NO ABUSE POTENTIAL
  o   ANTICONVULSANT PROPERTIES
            ANTICONVULSANTS

• CARBAMAZEPINE (TEGRETOL®)
  o   ADVERSE EFFECTS
       • NEUTROPENIA
       • THROMBOCYTOPENIA
       • HYPONATREMIA
             ANTICONVULSANTS

• CARBAMAZEPINE (TEGRETOL®)
  o   ALCOHOL WITHDRAWAL PROTOCOLS
       • 600 - 800 MG PER DAY IN DIVIDED DOSES
       • CONTINUE FOR 2 DAYS THEN DECREASE BY 200 MG PER
         DAY
             ANTICONVULSANTS

• TOPIRAMATE (TOPAMAX®)
  o   ORIGINALLY SYNTHESIZED AS ANTI-DIABETIC AGENT
  o   APPROVED FOR PARTIAL ONSET AND PRIMARY GEN.
      TONIC-CLONIC SEIZURES IN ADULTS AND CHILDREN
             ANTICONVULSANTS
• TOPIRAMATE (TOPAMAX®)
  o   I/2 LIFE 19-23 HOURS
  o   50-80% EXCRETED UNCHANGED IN THE URINE
  o   NO THERAPEUTIC RANGE OR BLOOD LEVEL MONITORING
             ANTICONVULSANTS
• TOPIRAMATE (TOPAMAX®)
  o   FOUND TO BE MORE EFFECTIVE THAN CONTROLS AND
      REDUCED THE NUMBER OF HEAVY DRINKING DAYS.
  o   STUDY MEASURED ABSTINENCE INITIATION NOT PERSISTENCE
       • PERHAPS DIFFERENT PHARMACOTHERPIES COULD BE USED FOR
         INITIATION, MAINTENANCE AND PROLONGED ABSTINENCE
       • WORK BY B.JOHNSON IN LANCET 2003;361;1677-1685.
             ANTICONVULSANTS
• TOPIRAMATE (TOPAMAX®) ADVERSE EFFECTS
  o   TRANSIENT PARESTHESIAS
  o   DECREASE COGNITION ( DECREASE IN CONCENTRATION AND
      MEMORY)
  o   SECONDARY ANGLE CLOSURE GLAUCOMA – RARE
  o   KIDNEY STONES (1.5% OR 2-4 TIMES THE GENERAL
      POPULATION)
  o   WEIGHT LOSS
  o   DECREASES ESTROGEN EFFECT OF BCP
  o   INCREASED HALDOL LEVEL
  o   TEGRETOL AND DILANTIN WILL DECREASE TMX LEVEL
                   ANTICONVULSANTS
•   TOPIRAMATE (TOPAMAX®) EVOLVING SPECTRUM OF USE
    o   EPILEPSY
    o   MIGRAINE PREVENTION
    o   ESSENTIAL TREMOR
    o   DIABETIC NEUROPATHIC PAIN
    o   MOOD DISORDERS
    o   ALCOHOL DEPENDENCE
    o   EATING DISORDERS
    o   PTSD
    o   TOURETTES SYNDROME
    o   OCD
    o   OBESITY
    o   TYPE 2 DIABETES
    o   NICOTINE DEPENDENCE
    o   COCAINE DEPENDENCE
                    BUPRENORPHINE



•    OVERVIEW OF THE DRUG ADDICTION TREATMENT ACT OF 2000
    - AN AMENDMENT TO THE CONTROLLED SUBSTANCES ACT
    (10/17/01)
    o   REVISION IN LEGISLATION ALLOWS PRACTITIONER TO PRESCRIBE
        NARCOTIC DRUGS IN SCHEDULE III, IV, V, OR COMBINATIONS OF
        SUCH DRUGS, FOR THE TREATMENT OF OPIOID DEPENDENCE
                        BUPRENORPHINE

•    OVERVIEW OF THE DRUG ADDICTION TREATMENT ACT OF 2000
    - AN AMENDMENT TO THE CONTROLLED SUBSTANCES ACT
    (10/17/01)
    o   PRACTITIONER REQUIREMENTS
         • “QUALIFYING PHYSICIAN”
             o   LICENSED
             o   BOARD CERTIFIED IN ADDICTION PSYCHIATRY
             o   CERTIFIED IN ADDICTION MEDICINE BY ASAM OR AOA
             o   INVESTIGATOR IN BUPRENORPHINE CLINICAL TRIALS
             o   8 HOURS OF DESIGNATED TRAINING
         • HAS CAPACITY TO REFER PATIENTS FOR APPROPRIATE COUNSELING
           AND ANCILLARY SERVICES
         • NO MORE THAN 30 PATIENTS (INDIVIDUAL OR GROUP) INITIALLY, CAN GO
           TO 100 AFTER ONE YEAR (MUST APPLY)
         • METHADONE CLINICS CAN HAVE UNLIMITED NUMBERS
                    BUPRENORPHINE


•   THEBAINE DERIVATIVE
    o   MAKES THIS LEGALLY CLASSIFIED AS AN OPIATE
•   PARTIAL OPIOID AGONIST
•   INITIALLY USED AS AN ANALGESIC
                    BUPRENORPHINE
• PARTIAL OPIOID AGONIST
   o   VERY HIGH AFFINITY FOR MU RECEPTOR
        • WILL DISPLACE MORPHINE, METHADONE
                      BUPRENORPHINE
• PARTIAL OPIOID AGONIST
   o   DESIRABLE PROPERTIES
        •   LOW ABUSE POTENTIAL
        •   LOWER LEVEL OF PHYSICAL DEPENDENCE
        •   SAFETY IF INGESTED IN OVERDOSE QUANTITIES
        •   WEAK OPIOID EFFECT AS COMPARED TO METHADONE
                    BUPRENORPHINE

• PARTIAL OPIOID AGONIST
   o   IF GIVEN TO A PATIENT MAINTAINED ON A FULL AGONIST, IT CAN
       PRECIPITATE AN ABSTINENCE SYNDROME DUE TO LOW
       EFFICACY AND DUE TO HIGH AFFINITY TO THE MU RECEPTOR
        • CANNOT EASILY OVERCOME THE BUPRENORPHINE EFFECT NOR
          CAN AN ANTAGONIST OVERCOME ITS EFFECT.
                     BUPRENORPHINE

• PHARMACOLOGIC USES
  o   POTENT ANALGESIC
       • AVAILABLE IN MANY COUNTRIES AS A SUBLINGUAL TABLET (0.3 - 0.4
         MG) CALLED TEMGESIC®
       • AVAILABLE IN THE U.S. AS AN PARENTERAL FORM CALLED
         BUPRENEX®
       • LOW DOSES FOR PAIN TREATMENT AS COMPARED TO ADDICTION
         TREATMENT ( 0.3 - 0.6 MG IM OR IV Q 6 HOURS)
                   BUPRENORPHINE

• PHARMACOLOGIC USES
  o   POOR ORAL BIOAVAILABILITY
       • SUBLINGUAL WITH ABSORPTION THROUGH THE ORAL MUCOSA
  o   SLOW DISSOCIATION RATE
       • PROLONGED THERAPEUTIC EFFECT - SO CAN BE GIVEN EVERY
         OTHER OR EVERY THIRD DAY
                         BUPRENORPHINE

• PHARMACOLOGIC USES
  o   TREATMENT OF ADDICTIONS*
       •   IN THE U.S.
            o   2 & 8 MG SUBLINGUAL TABLETS MADE BY RECKITT & COLMAN CALLED
                SUBUTEX®
            o   2 & 8 MG SUBLINGUAL TABLETS WITH NALOXONE IN A 4:1 RATIO CALLED
                SUBOXONE®
                     BUPRENORPHINE

• PHARMACOLOGIC USES
  o   DOSES USED FOR OPIOID ADDICTION TREATMENT IS 1 -2
      MG UP TO 16 - 32 MG
  o   DURATION IS A FEW WEEKS TO YEARS?
       • SHORT-TERM TREATMENT IN ADOLESCENTS?
           o JAMA article by G. Woody et al, (2008) adolescents aged 15 to 21
             did better with long term Suboxone than a short (2 week) detox
             protocol using Suboxone
  o   TO REDUCE POTENTIAL FOR ABUSE THE COMBINATION
      TABLET WAS MADE
       • WORKS ON PRINCIPLE THAT NALOXONE IS 100 TIMES MORE
         POTENT BY INJECTION THAN BY THE SUBLINGUAL ROUTE
           o   IF TAKEN S.L. BUP>>>>>>NALONXONE
           o   IF TAKEN I.V. NALOXONE>>>>>BUP
                    BUPRENORPHINE
• SAFETY
  o   IF SWALLOWED ACCIDENTIALLY BY A NON- PHYSICALLY
      DEPENDENT PERSON DUE TO POOR ORAL BIOAVAILABILITY
      THERE IS VIRTUALLY NO OPIOID EFFECT IN ADULT – PEDIATRIC
      CASES OF OVERDOSE
  o   REPORT OF 53 CASES OF HEPATITIS IN FRANCE SINCE 1996.
      ALL INVOLVED IV BUPRENORPHINE WHICH LEAD TO HEPATITIS
       • PERHAPS DUE TO INCREASE BIOAVAILABILITY IF TAKEN IV
                 BUPRENORPHINE

• SIDE EFFECTS
  o   SIMILAR TO OTHER MU AGONISTS THOUGH LESS SO
       • NAUSEA
       • VOMITING
       • CONSTIPATION


  *NO DISRUPTION IN COGNITIVE AND PSYCHOMOTOR
    PERFORMANCE
                   BUPRENORPHINE

• TERATOGENESIS
  o   LIMITED REPORTS
       • ONE STUDY FOUND NO SIGNS OF PHYSICAL DEPENDENCY IN
         NEONATES OF HEROIN ADDICTED MOTHERS TAKING
         BUPRENORPHINE
                   BUPRENORPHINE

• DRUG INTERACTIONS
  o   SCANT STUDIES
  o   DEATH CASE REPORT ASSOCIATED WITH IV BUPRENORPHINE
      AND BENZODIAZEPINES
  o   CANNOT GIVE WITH ReVia
  o   AVOID MEDICATIONS THAT ARE METABOLIZED BY THE
      CYTOCHROME P450 3A4 SYSTEM
  o   IF ACUTE PAIN TREATMENT IS NEEDED, MAY HAVE TO SWITCH
      TO METHADONE
                      On the Horizon

• Implantable buprenorphine – Probuphine
   o   6 month duration
   o   Being studied by Dr. Walter Ling at UCLA
        • 108 patients and 55 placebo patients
        • 40% in bup group and 28% in placebo group tested negative for
          illegal drugs at 16 weeks.
        • At 24 weeks 66% of treatment group compared to 31% in placebo
          group were still in treatment


• Buprenorphine patch
   o   For pain and not addiction – much different dosing
         NALOXONE (NARCAN)
• Opioid antagonist which reverses opioid overdoses
• Pushes most other opioids off the receptors, then sits on
  the receptor preventing it from being activated for 30-90
  minutes
• Analogy - getting the wrong key stuck in a lock
         NALOXONE IN ACTION

• Reverses sedation and respiratory depression
• Causes sudden withdrawal in the opioid dependent
  person
• No psychoactive effects
• Over the counter in some countries, but not the US
• Routinely used by EMS
             ADMINISTRATION
• Inject into muscle but subcutaneous and intravenous are
  fine also
• Acts in 2-8 minutes
• If no response in 2-5 minutes repeat- and if 911 has not
  been called do it now!!
• Do not repeat naloxone more than twice
• Lasts 30-90 minutes
http://www.health.state.ny.us/diseases/aids/harm_reduction/opioidprevention/index.htm
      NICOTINE REPLACEMENT THERAPIES (NRT)



• CORNERSTONE OF TOBACCO DEPENDENCE
  TREATMENT
  o   SAFE
  o   EFFECTIVE
             SMOKING CESSATION
• 70 MILLION SMOKERS IN
  THE US
   o   90% WOULD LIKE TO QUIT
   o   60% HAVE TRIED TO QUIT
   o   66% HAVE HEALTH
       CONCERNS


 HIGH MOTIVATION BUT LIMITED
           SUCCESS
1634 RUSSIA: CZAR ALEXIS
  CREATES PENALTIES FOR
  SMOKING: 1ST OFFENSE IS
  WHIPPING, A SLIT NOSE,
  AND TRASPORTATION TO
  SIBERIA.
• 1634 RUSSIA: 2ND OFFENSE IS EXECUTION
  SMOKING CESSATION METHODS
• UNASSISTED
  o   COLD TURKEY
  o   WARM CHICKEN
       • INTAKE LIMITED
       • BRAND CHANGING
  o   NONPRESCRIPT. AIDS
       • NICO BLOC
                                       NicoBloc
•   A completely natural product
•   viscous liquid you apply directly to your
    cigarette filter.
      o   The main ingredients of consist of:
          water, a sugar compound, citric acid,
          food coloring and preservatives.
      o   Approved by FDA
             • $49.97 - In each pack there is one
                bottle of NicoBloc which contains
                approximately 700 drops.
•   In the first week of using NicoBloc, you
    apply ONE drop of NicoBloc to the filter of
    EACH cigarette you smoke. This reduces
    the amount of tar and nicotine you inhale by
    up to 33%.
•   In week two you use TWO drops of NicoBloc
    on the filter of EACH cigarette you smoke.
    This reduces the amount of tar and nicotine
    you inhale by up to 66%.
•   Week three onwards, you apply THREE
    drops of NicoBloc to EACH cigarette you
    smoke.
SMOKING CESSATION METHODS
 • ASSISTED
   o   SUPPORT GROUPS
   o   COMMERCIAL PROGRAMS
   o   ACUPUNCTURE
   o   MD ASSISTED CESSATION
     Findings and Recommendations of US Public Health Service Clinical
                      Practice Guidelines (June 2000)


5. There is a strong dose-response relation between the intensity of
   tobacco dependence counseling and its effectiveness.
   Treatments involving person-to-person contact (via individual,
   group, or proactive telephone counseling) are consistently
   effective, and their effectiveness increases with treatment intensity
   (e.g., minutes of contact).




                                                                           117
Efficacy of Various Intensity Levels of Person-to-Person Contact (n =
                              43 studies)


                                                     Estimated
    Level of Contact                               Abstinence Rate
     No contact                                         10.9%
     (reference group)

   Minimal counseling                                   13.4%
   (< 3 minutes)
  Low intensity counseling
                                                        16.0%
  (3-10 minutes)
Higher intensity counseling                             22.1%
(> 10 minutes)
                                                                        118
MD SUPPORTED TREATMENT




             National Cancer Institute
      MD SUPPORTED TREATMENT
• AVERSIVE CONDITIONING
• NICOTINE ANTAGONIST??
  o   MECAMYLAMINE
      NICOTINE REPLACEMENT THERAPIES (NRT)


• DEVELOPED IN SWEDEN DURING THE 1970”S AS A
  MEANS TO ASSIST SUBMARINERS
• CORNERSTONE OF TOBACCO DEPENDENCE
  TREATMENT
  o   SAFE
  o   EFFECTIVE
         NICOTINE REPLACEMENT THERAPIES (NRT)

•   NICOTINE GUM (NICOTINE
    POLACRILEX, NICORETTE®
     o  FDA APPROVAL 1984
     o  AVAILABLE IN 2MG AND 4MG
          •   .86 MG ABSORBED FROM THE 2MG
              PIECE
          •   1.2 MG ABSORBED FROM THE 4 MG
              PIECE
     o   COMPOSED OF NICOTINE BOUND
         TO AN ION-EXCHANGE RESIN
         INCORPORATED INTO A GUM BASE
     o   “PARK AND CHEW” TECHNIQUE
     o   AFFECTED BY CHEWING RATE
         AND pH OF THE SALIVA
     o   ADVERSE EFFECTS: JAW PAIN,
         MOUTH SORENESS, DYSPEPSIA,
         HICCUPS
        NICOTINE REPLACEMENT THERAPIES (NRT)

•   NICOTINE TRANSDERMAL
    PATCHES (HABITOL®, NICODERM
    CQ ®, NICOTROL ® )
    o   APPROVED BY THE FDA IN 1991
    o   OTC APPROVAL IN 1996
    o   ALL 21 MG PATCHES DELIVER .9MG OF
        NICOTINE PER HOUR
    o   TEMPERATURE AND CIRCULATION
        AFFECT DELIVERY
    o   ADVERSE EFFECTS: SLEEP
        DISTURBANCE, SKIN REACTIONS
        NICOTINE REPLACEMENT THERAPIES (NRT)


•   NICOTINE INHALER
    (NICOTROL INHALER ® )
    o   FDA APPROVED IN 1998
    o   CIGARETTE HOLDER SHAPE
        WITH REPLACEABLE
        CARTRIDGES
         •   EACH CONTAINS 10 MG
             NICOTINE AND 1 MG MENTHOL
         •   400 PUFFS PER CARTRIDGE
             DELIVERING 13 UG PER PUFF
         •   80 PUFFS EQUAL ONE
             CIGARETTE
         •   USE 4 - 6 INHALERS PER DAY
    o   AFFECTED BY PUFF RATE,
        TEMPERATURE, SALIVA pH
    o   25% TAPER EVERY MONTH IN
        NUMBER OF PUFFS
         NICOTINE REPLACEMENT THERAPIES (NRT)



•   NICOTINE SPRAY ( NICOTROL NS ® )
     o APPROVED BY THE FDA IN 1996
     o ONE INHALATION IN EACH
       NOSTRIL = TOTAL DOSE OF 1MG
     o AVERAGE USE IS 13 - 20 DOSES
       PER DAY
     o ADVERSE EFFECTS: RUNNING
       NOSE, NASAL IRRITATION,
       THROAT IRRITATION, WATERY
       EYES, SNEEZING
         • ALL BUT THROAT IRRITATION
           DECREASE IN 1 - 7 DAYS
         NICOTINE REPLACEMENT THERAPIES (NRT)


•   NICOTINE LOZENGE (COMMIT ® )
     o  APPROVED BY THE FDA IN 2002,
        THOUGH DESCRIBED AS EARLY
        AS THE 1960’S
     o  2MG AND 4 MG DOSES
     o  MAXIMUM NUMBER IS 20
        LOZENGES PER DAY
          •   Dosage
                  o    2 mg-for those smoking >30 min after
                       waking
                   o   4 mg-for those smoking <30 min after
                       waking
          •   First 6 weeks 1 lozenge every 1-2 hrs
          •   Weeks 7-10 1 lozenge every 2-4 hrs
          •   Weeks 11-12 1 lozenge every 4-8 hrs


     o   GLAXO PACKAGES “TIME TO FIRST
         CIGARETTE” PROGRAM WITH
         LOZENGES - PROGRAM TO
         DECIDE IF PATIENT SHOULD
         START WITH A 2 OR 4 MG
         LOZENGE
         Efficacy of Nicotine Gum
                (n = 13 studies)

                                    Estimated
                                    Abstinence
Pharmacotherapy                       Rate

 Placebo
                                       17.1%
 (reference group)

                                      23.7%
 Nicotine Gum

                                                 127
      Efficacy of Nicotine Inhaler
              (n = 4 studies)

                              Estimated
Pharmacotherapy             Abstinence Rate

 Placebo
                                10.5%
 (reference group)

                                22.8%
 Nicotine Inhaler


                                              128
         Efficacy of Nicotine Nasal Spray
                    (n = 3 studies)



                                   Estimated
Pharmacotherapy                  Abstinence Rate

  Placebo                             13.9%
  (reference group)

  Nicotine Nasal                      30.5%
  Spray
                                                   129
           Efficacy of Nicotine Patch
                 (n = 27 studies)



                                    Estimated
Pharmacotherapy                   Abstinence Rate

Placebo                                 10.0%
(reference group)

                                        17.7%
 Nicotine Patch

                                                130
        Efficacy of Combination NRT
               (n = 3 studies)


                              Estimated
Pharmacotherapy             Abstinence Rate

One NRT (reference               17.4%
group)

  Two NRTs                       28.6%




                                              131
       NICOTINE REPLACEMENT THERAPIES (NRT)


• NICOWater
   o   Illegal in NYS
   o   Can easily be sold to minors
OTHER NICOTINE PRODUCTS




            ONE DOSE IS EQUAL TO
            1 MG NICOTINE
            FROM TOBACCO
            NEW NICOTINE REPLACEMENT

•   THE STRAW™
     o 8 MG – NICOTINE BITARTRATE
       BEADS
     o ORAL DELIVERY
         • AN INDIVIDUAL SIPS ANY
           BEVERAGE THROUGH THE
           STRAW™ AND SWALLOWS
           THE NICOTINE BEADS
         • THE ENTIRE DOSE OF
           NICOTINE IS DELIVERED IN
           THE FIRST SIP
     o MANUAL STIMULI
     o INCREASED COMPLIANCE
     o BEHAVIORAL COMPONENT

•   RECOVERY PHARMACEUTICALS
     o PHASE 1 & 2 COMPLETED
     o PHASE 3 - UNDERWAY
    A new type of tobacco free, nicotine delivery
              system – E Cigarettes
•    Generally, e-cigarettes required stronger vacuums
     (suction) to smoke than conventional brands, and
     the effects of this on human health could be
     adverse.
•    The amount of aerosol produced by e-cigarettes
     decreased during smoking, which necessitated
     increasing puff strength to produce aerosol. The
     decreased efficiency of aerosol production during e-
     cigarette smoking makes dosing nonuniform over
     time and calls into question their usefulness as
     nicotine delivery devices.
       o    The vacuum required to smoke conventional cigarettes
            varied among the eight brands tested. Lights and ultra-
            light brands required stronger vacuums to smoke than
            unfiltered and regular filtered brands.
       o    Except for one brand, higher vacuums were required to
            smoke e-cigarettes than conventional brands.
       o    Smoke/aerosol density was stable for conventional
            brands and for e-cigarettes over the first 10 puffs;
            however, aerosol density of e-cigarettes dropped
            during subsequent smoking, and higher vacuums were
            required to produce aerosol as the puff number
            increased. While conventional cigarettes were uniform
            in their smoking behavior within brands, vacuum and
            density varied within brands of e-cigarettes.



•    ATrtchounian et al, Nicotine and Tobacco Research July 2010



                                                                      USB powered E Cigarette
                          ZYBAN®

•   GENERIC FORM= BUPROPION HYDROCHLORIDE
•   MARKETED FIRST AS AN ANTIDEPRESSANT
    o   WELLBUTRIN® & WELLBUTRIN SR ®
•   FIRST NON-NICOTINE MEDICATION APPROVED FOR SMOKING
    CESSATION
•   150 MG BID
                          ZYBAN®

•   APPEARS TO WORK THRU THE DOPAMINE AND
    NOREPINEPHRINE PATHWAYS TO REDUCE CRAVING THOUGH
    NEWER WORK POINTS TO IT ALSO BEING A NICOTINE
    RECEPTOR ANTAGONIST
•   CAN BE USED ALONE OR IN COMBINATION WITH NICOTINE
    REPLACEMENT MEDICATIONS
•   SIDE EFFECTS
    o   DRY MOUTH
    o   INSOMNIA
    o   NEJM 2002 – SEIZURE INDUCED BY INSUFFLATION OF BUPROPION –
        CASE REPORT OF ADOLESCENT WHO CRUSHED SIX 150MG
        TABLETS AND SNORTED THEM
                  VARENICLINE

• Varenicline is a drug which stimulates nicotine receptors
  in the brain without itself being addictive.
• Developed by Pfizer Pharmaceuticals, varenicline is a
  nicotine partial receptor agonist which comes in pill form
  to prevent withdrawal symptoms in people attempting to
  quit smoking.
• Warnings about suicidal ideations and increased cardiac
  events if smoker has a cardiac problem
    Results of 12-week phase 2 varenicline dosing trial (n =
                            627)

•    4 doses evaluated:
      o   .5 mg and 1.0 mg twice daily titrated
      o   .5 mg and 1.0 mg twice daily non-titrated.
•    Weeks 9-12 continuous abstinence rates pooled by dose.
      o   1.0 mg twice daily doses      = 50.6%
      o   0.5 mg twice daily doses      = 45.1%
      o   Placebo               = 12.4%




    1Oncken C, et al. (2005). Presented at the 2005 Meeting of the Society for Research on Nicotine and
    Tobacco. Prague, Czech Republic.
  Special
Populations
           Cannabis Dependence

• Numerous studies indicate that cannabis use among
  methadone maintenance patients does not lead to worse
  outcomes.
• No specific medications to treat Cannabis Dependence
• CBT effective for patients who want to quit
• Use Motivational Interviewing for patients who do not
  want to quit
• Gabapentin seems to show some progress
         Benzodiazepine Dependence
• Gradual taper of primary sedative drug with more rapid
  taper for first 50% of dose and more slowly for each
  successive 25%
• Clonazepam (Klonopin)taper for short acting
  benzodiazepines
• Carbamazepine 200 – 800 mg daily or valproic acid 250
  mg tid along with benzodiazepine for first 1 – 2 weeks,
  then taper benzo over 4 weeks; continue anticonvulsant
  alone for 2 – 4 weeks
   o   Buprenorphine may have a drug – drug interaction with
       carbamazepine
• Cognitive behavioral therapy significantly increases
  success rate
              Cocaine Dependence

•   Need more randomized studies
•   Need agents that can increase dopamine and NE
•   Need to affect the glutamate system
•   No medications approved as yet
                Cocaine Dependence

• N-acetyl – cystenine
   o   Used in Tylenol ovedose, mucolytic agent
   o   Source of cysteine which can restore glutamate levels seen in
       cocaine withdrawal
• Modafinil
   o   Wake promoting agent
   o   Non-amphetamine stimulant
   o   Increase levels of glutamate and decreased levels of GABA
   o   Low abuse potential
• Topiramate
   o   anticonvulsant
                Cocaine Dependence

• Vigabatrin (Gamma – Vinyl- GABA)
   o   Atypical seizure med
• Baclofen
   o   GABA agonist
• Tiagabine
   o   Anticonvulsant
• Antabuse
   o   Inhibit Dopamine Beta-Hydroxylase so increased dopamine
       levels
• Bupropion
   o   Dopamine and NE reuptake inhibitor
                           Gambling

• Naltrexone and Nalmefine
   o   Opiate antagonists which will block the high
• Have tried antidepressants and mood stabilizers
   o   Paxil worked in one trial and not another
   o   If bipolar, then mood stabilizers may work
                          Binge Drinking

• 5/4 rule: 5 drinks in men, 4 in women in a short period of
  time or one sitting
   o   Acamprosate – anticraving
   o   Antabuse - ???
   o   Newest regimen:
        • Naltrexone is first choice as decreases high and impulsivity
        • If fail, add low dose Ondansetron to Naltrexone
            o   8 ug/Kg is much lower than dosing for anti-emetic effect and is not
                available yet
•   NICVAX ™ (NICOTINE CONJUGATE VACCINE) A NOVEL AND PROPRIETARY
    INVESTIGATIONAL VACCINE TO PREVENT AND TREAT NICOTINE ADDICTION
    AND AS AN AID TO SMOKING CESSATION.
•   IN AUGUST 2003, NABI BIOPHARMACEUTICALS INITIATED A PHASE II
    CLINICAL TRIAL OF NICVAX IN THE U.S. THIS DOUBLE-BLIND, RANDOMIZED,
    PLACEBO-CONTROLLED STUDY IN 63 SMOKERS
     o  NICVAX IS DESIGNED TO CAUSE THE IMMUNE SYSTEM TO PRODUCE
        ANTIBODIES THAT BIND TO NICOTINE AND PREVENT IT FROM ENTERING
        THE BRAIN.
•   The Hebrew University researchers, led
    by Dr. Rami Yaka of the university's
    Institute of Drug Research, were
    seemingly able to erase the drug-linked
    memories of rats that had been
    deliberately administered cocaine over
    two weeks' time.
•   The researchers injected a small protein -
    a peptide called ZIP - directly into an area
    of the addicted rats' basal forebrain
    called the nucleus accumbens, which
    controls pleasure and reward and which
    has been demonstrated to be connected
    to drug addiction.
•   Afterward, the rats were returned to their
    pens to check their reactions. Rather
    than seeking out the place where they
    had been getting their "fixes" of cocaine,
    the rats ignored it, indicating that
    memories linked to their addiction had
    been erased.
    LASER TREATMENT FOR SMOKING

•   A company called Advanced Laser
    Therapy claims to be able to get
    smokers to quit in 30 minutes through
    the use of laser treatment
•
    The laser stimulates endorphins and
    fools the body into thinking the patient
    is smoking.
      o  The laser is used at various points
         of the body -- ears, wrist, and leg,
         among others -- to flush nicotine
         from the system. The flushing
         process continues over several
         days as patients drink copious
         amounts of water to clean out
         their system.
      o  The laser treatment, which costs
         $275, is currently in clinical trials
         as the company seeks FDA
         approval.
09/2005
ADDICTION MEDICATIONS
   ARE FOR THE BRAIN,
12 STEP IS FOR THE SOUL.
stevenkipnis@oasas.ny.gov

								
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